DEFECTIVE PEROXISOME BIOGENESIS WITH A NEUROMUSCULAR DISORDER RESEMBLING WERDNIG-HOFFMANN-DISEASE

Objective: Characterization of the defect in a patient presenting a pe ripheral neuropathy with atypical features of distal motor involvement mimicking Werdnig-Hoffmann disease. Patient: Clinical signs included generalized hypotonia and floppiness, absence of stretch reflexes, mus cle wasting, lack of head control and lingual fasciculations associate d with unaffected facial muscles, and normal intellectual development. Results: Normal muscle histology ruled out Werdnig-Hoffmann disease. Elevated plasma concentrations of very long-chain fatty acids and bile acid intermediates combined with normal plasmalogen levels in erythro cytes suggested defective peroxisomal beta-oxidation directly demonstr ated by deficient pristanic acid and partially deficient C26:0 was pre sent oxidation in cultured fibroblasts. Severely impaired pipecolic ac id oxidation in liver and phytanic acid oxidation in fibroblasts was p resent. On light and electron microscopy of the liver tissue, rare per oxisomal membrane ghosts and trilamellar inclusions but absence of per oxisomes was noted. Immunoblot analysis revealed absence of peroxisoma l beta-oxidation enzymes in liver tissue but normal results in fibrobl asts. Remarkably, expression of the peroxisomal defect in fibroblasts was indicated by the finding of mainly cytoplasmatic catalase, as in l iver. Preliminary studies excluded classification of this patient with in the large PEX1 complementation group. Conclusions: The results sugg est a novel peroxisome biogenesis disorder involving peroxisomal beta- oxidation as well as phytanic and pipecolic acid oxidation rather than an isolated defect of peroxisomal beta-oxidation. The association of a clinical picture mimicking Werdnig-Hoffmann disease with a novel per oxisomal disorder raises the question of whether investigation for per oxisomal function should be considered in every patient with an enigma tic spinal muscular atrophy-like syndrome.